Cationic Galactose-Conjugated Copolymers for Epidermal Growth Factor (EGFR) Knockdown in Cervical Adenocarcinoma

Glycopolymers of statistical and block configurations were synthesized from 2-lactobionamidoethyl methacrylamide (LAEMA) and 2-aminoethyl methacrylamide hydrochloride (AEMA) by the reversible addition–fragmentation chain transfer (RAFT) polymerization. These cationic glycopolymers were found to form very stable polyplexes with EGFR siRNA as determined by dynamic light scattering and agarose gel electrophoresis. The polyplexes revealed to be very stable even in the presence of serum proteins. Transfection studies of the glycopolymer-EGFR siRNA polyplexes were achieved in HeLa cells to determine the EGFR knockdown efficiency, cellular uptake and cytotoxicity. In this study, the block copolymer with the shortest AEMA segment was the most effective in EGFR gene silencing, however this block copolymer revealed to be slightly more toxic as compared to the statistical copolymers studied at higher w/w ratios. In addition, gene silencing of up to 80–85% was achieved with this low-molecular-weight block copolymer

Upsell_Downsell_Follow_up_Survey_-_Brands_Removed – Supplemental material for Assessing the Customer-Based Impact of Up-Selling Versus Down-Selling

<p>Supplemental material, Upsell_Downsell_Follow_up_Survey_-_Brands_Removed for Assessing the Customer-Based Impact of Up-Selling Versus Down-Selling by Tim Norvell, Piyush Kumar, and Sunil Contractor in Cornell Hospitality Quarterly</p

Upsell_Downsell_Survey_-_Brands_Removed_Supplement – Supplemental material for Assessing the Customer-Based Impact of Up-Selling Versus Down-Selling

<p>Supplemental material, Upsell_Downsell_Survey_-_Brands_Removed_Supplement for Assessing the Customer-Based Impact of Up-Selling Versus Down-Selling by Tim Norvell, Piyush Kumar, and Sunil Contractor in Cornell Hospitality Quarterly</p

Asialoglycoprotein Receptor-Mediated Gene Delivery to Hepatocytes Using Galactosylated Polymers

Highly efficient, specific, and nontoxic gene delivery vector is required for gene therapy to the liver. Hepatocytes exclusively express asialoglycoprotein receptor (ASGPR), which can recognize and bind to galactose or N-acetylgalactosamine. Galactosylated polymers are therefore explored for targeted gene delivery to the liver. A library of safe and stable galactose-based glycopolymers that can specifically deliver genes to hepatocytes were synthesized having different architectures, compositions, and molecular weights via the reversible addition–fragmentation chain transfer process. The physical and chemical properties of these polymers have a great impact on gene delivery efficacy into hepatocytes, as such block copolymers are found to form more stable complexes with plasmid and have high gene delivery efficiency into ASGPR expressing hepatocytes. Transfection efficiency and uptake of polyplexes with these polymers decreased significantly by preincubation of hepatocytes with free asialofetuin or by adding free asialofetuin together with polyplexes into hepatocytes. The results confirmed that polyplexes with these polymers were taken up specifically by hepatocytes via ASGPR-mediated endocytosis. The results from transfection efficiency and uptake of these polymers in cells without ASGPR, such as SK Hep1 and HeLa cells, further support this mechanism. Since in vitro cytotoxicity assays prove these glycopolymers to be nontoxic, they may be useful for delivery of clinically important genes specifically to the liver

Thickness and Stacking Dependent Polarizability and Dielectric Constant of Graphene–Hexagonal Boron Nitride Composite Stacks

The giant carrier mobility of graphene is significantly reduced due to external perturbations, such as substrate based charge impurities, and their impact can be minimized by encapsulating graphene between hexagonal boron nitride (hBN) layers. Using density functional theory (DFT) based ab initio calculations, we study the static response of such a composite by placing it in a vertical electric field. We find that at relatively low electric field (∼0.1 V/Å), although the relative permittivity (ε_r) of a composite stack increases with the number of layers, ε_r for a fixed stack thickness is independent of the field strength. However, at higher electric field strength, ε_r increases monotonically with the applied field strength even for a fixed stack thickness, signifying nonlinear response. The relative permittivity changes more readily for graphene rich stacks as compared to hBN rich stacks, which is consistent with the property of the pristine phases. We also present an empirical formulation to calculate the thickness and stacking dependent effective dielectric constant of any arbitrary stack of graphene–hBN layers, which fits very well with the ab initio calculations. Our empirical formulation will also be applicable for van der Waals stacks of other two-dimensional materials and will be useful for designing and interpreting transport experiments, where electrostatic effects such as capacitance and charge screening are important

Galactose-based Thermosensitive Nanogels for Targeted Drug Delivery of Iodoazomycin Arabinofuranoside (IAZA) for Theranostic Management of Hypoxic Hepatocellular Carcinoma

In this study, galactose-based nanogels were prepared by reversible addition–fragmentation chain transfer process to facilitate the targeted delivery of iodoazomycin arabinofuranoside (IAZA), a clinical drug for imaging solid hypoxic tumors, and evaluate its role in hypoxia-selective (radio)­theranostic (therapy + diagnostic) management of therapy-resistant cancer cells. The nanogels have a cross-linked temperature-responsive core and a dense carbohydrate shell. Their thermoresponsive nature allowed the controlled encapsulation of IAZA drug for targeted delivery and release in hypoxic hepatocellular carcinoma via asialoglycoprotein receptor-mediated uptake. The synthesized nanogel-IAZA delivery systems demonstrated a stable, nonburst release of IAZA over 10 h with up to 0.6 mM loading capacity of IAZA within the nanogel. The cytotoxicity evaluations of the nanogels demonstrated that they are relatively nontoxic in multiple cell lines. The radiosensitization studies indicated that IAZA in encapsulated form offers a superior radiosensitization of hypoxic cells (sensitizer enhancement ratio for IAZA alone, 1.33; 1.62 for nanogel encapsulated IAZA). These studies suggest that galactose-based nanogels may serve as a versatile drug delivery system for IAZA (and other azomycin-based agents) and enable its hypoxia-selective multimodal theranostic applications to manage hypoxic solid (hepatocellular) tumors by facilitating position/single photon emission tomography-based imaging, external beam radiation therapy, and <i>in situ</i> molecular radiotherapy

Synthesis and Evaluation of Polymeric Gold Glyco-Conjugates as Anti-Cancer Agents

The antitumor activity of organo-gold compounds is a focus of research from the past two decades. A variety of gold stabilizing ligands such as vitamins and xanthanes have been prepared and explored for their ‘chelating effect’ as well as for their antitumor activity. Dithiocarbamates (DTC) compounds and their metallic conjugates have been well explored for their antiproliferative activities. In this study, glycopolymer based DTC-conjugates are prepared by reversible addition–fragmentation chain transfer polymerization (RAFT) and subsequently modified with gold­(I) phosphine. These polymer-DTC derivatives and their gold compounds are tested for their <i>in vitro</i> toxicity in both normal and cancer cell lines. The Au­(I) phosphine conjugated cationic glycopolymers of 10 kDa and 30 kDa are evaluated for their cytotoxicity profiles using MTT assay. Au­(I) compounds are well-known for their mitochondrial toxicity, hence hypoxic cell lines bearing unusually enlarged mitochondria are subjected to these anticancer compounds. It is concluded that these polymeric DTC derivatives and their gold conjugates indeed show higher accumulation as well as cytotoxicity to cancer cells under hypoxic conditions in comparison to the normoxic ones. Hypoxic MCF-7 cells showed significant sensitivity toward the low molecular weight (10 kDa) glycopolymer-Au­(I) complexes

Synthesis and Evaluation of Glycopolymeric Decorated Gold Nanoparticles Functionalized with Gold-Triphenyl Phosphine as Anti-Cancer Agents

In this study, statistical glyco-dithiocarbamate (DTC) copolymers were synthesized by reversible addition–fragmentation chain transfer polymerization (RAFT) and subsequently used to prepare glyconanoparticles and conjugated glyconanoparticles with the anticancer drug, gold­(I) triphenylphosphine. These glyconanoparticles and the corresponding conjugates were then tested for their in vitro cytotoxicity in both normal and cancer cell lines using Neutral Red assay. The glyconanoparticles and their Au­(I)­PPh₃ conjugates were all active against MCF7 and HepG2 cells, but galactose-functionalized glyconanoparticles {P­(GMA-EDAdtc­(AuPPh₃)-st-LAEMA)­AuNP} were found to be the most cytotoxic to HepG2 cells (IC₅₀ ∼ 4.13 ± 0.73 μg/mL). The p­(GMA-EDAdtc­(AuPPh₃)-st-LAEMA)­AuNP was found to be a 4-fold more potent antitumor agent in HepG2 cells, and the overexpressed asialoglycoprotein (ASGPR) receptors revealed to play an important role in the cytotoxicity, presumably by the enhanced uptake. In addition, the glyconanoparticles Au­(I) conjugates are found to be significantly more toxic as compared to the standard chemotherapeutic reagents such as cisplatin and cytarabine